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Review
. 2023 Apr;601(8):1319-1341.
doi: 10.1113/JP284137. Epub 2023 Mar 13.

A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth

Catherine G Dimasi  1 , Jack R T Darby  1 , Janna L Morrison  1
Affiliations
Review

A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth

Catherine G Dimasi et al. J Physiol. 2023 Apr.

Abstract

Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease.

Keywords: biomarkers; fetal development; heart attack; heart disease; miRNA; programming; regeneration.

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Conflict of interest statement

The authors have no conflicts of interest.

Figures

Figure 1
Figure 1. Cardiomyocyte transition from proliferation to quiescence occurs at different times in zebrafish, rodents and large mammals
During embryonic development, when oxygen is low (deep blue section of arrow), CMs undergo proliferation (green bars) and remain mononucleated. Postnatal CMs in zebrafish remain proliferative throughout life despite low oxygen, whilst rodent CMs exit the cell cycle and become non‐proliferative (red bars) within 3−7 days after birth when oxygen increases (lighter blue arrow). In contrast, this transition event occurs during late gestation in large mammals when oxygen levels are low. Heart volume can only increase by hypertrophic growth of pre‐existing CMs and mononucleated CMs become binucleated or in the case of pigs even multinucleated. Adapted from Lock et al. (2018).
Figure 2
Figure 2. Cortisol and thyroid hormone concentrations and resulting cardiomyocyte number and binucleation after birth in rats and in late‐gestation sheep fetuses
In rats, there is a steep surge in circulating corticosterone and thyroid hormone (T3) postnatally at P10, leading to a proliferative burst of CMs at P15. In sheep, the surge in cortisol and circulating T3 occurs during late gestation (∼135–145d GA), which coincides with the cessation of proliferation and rise in binucleation in CMs.
Figure 3
Figure 3. Regulation of the fetal cardiac cell cycle by miRNAs
There is a complex interplay of miRNA regulation and the cell cycle. The miRNA‐15 family, the Let‐7 family, miRNA‐240 and miRNA‐302 are miRNAs that inhibit CDK/cyclin complexes at various points in the cell cycle. The miRNA‐17/92 cluster, miRNA‐302/376 cluster, miRNA‐199‐3p and miRNA‐590‐3p negatively regulate cell cycle inhibitors allowing for proliferation. Note many more miRNAs interact with the cell cycle and this figure represents a simplified version.
Figure 4
Figure 4. Regulation of cardiac metabolism by miRNAs before and after birth
miRNAs regulate many aspects of glucose and lipid metabolism in the heart. miRNA‐133, ‐150, ‐155 and ‐223 and the Let‐7 family regulate glucose transport via modulating the expression of GLUT4. miRNA‐27a‐3p, ‐125b, ‐135 and ‐199a promote glycolysis whilst miRNA‐138 has been shown to inhibit the glycolysis pathway. miRNA‐195 increases acylation of pyruvate dehydrogenase (PDH) to promote conversion of pyruvate to acetyl‐CoA. The Let‐7 family promotes FAO whilst miRNA‐33a/b, ‐132 and ‐212 repress various enzymes involved in the pathway. miRNA‐140, ‐499 and ‐761 regulate the TCA cycle inside the mitochondria, and miRNA‐181c and miRNA‐210 are involved in ETC remodelling via suppression of complex 2 (SDHB) and 4 (MTCO1). Note many more miRNAs interact with the metabolic pathways and this figure represents a simplified version.
Figure 5
Figure 5. Overview of the formation and release of exosomes from cells and their use as biomarkers of disease
Numerous diseases including heart disease, brain/neurodegenerative disease, renal disease, cancer and even physiological alterations such as pregnancy can be detected via miRNAs packaged into circulating exosomes released into the bloodstream or other bodily fluids such as saliva and urine. Circulating exosomal miRNAs are an attractive diagnostic target due to their non‐invasive nature.
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